In a Time of Flight mass spectrometer bunches of ions are caused to enter a field free flight region with essentially the same kinetic energy. Ions with different mass to charge ratios will therefore travel with different velocities through the flight region and will reach a detector arranged at the end of the flight region at different times. The mass to charge ratios of the ions can then be determined by determining the transit times of the ions through the flight region.
Microchannel Plate (“MCP”) detectors, discrete dynode electron multipliers or combinations of these devices are most commonly used as ion detectors in Time of Flight mass spectrometers. These detectors produce a bunch of electrons in response to an ion arriving at the ion detector. The electrons produced by the ion detector in response to an ion arrival are collected on one or more collection electrodes or anodes which are connected to a charge sensing discriminator. The signal produced by the charge sensing discriminator in response to electrons striking the collection electrode is commonly recorded using a multi stop Time to Digital Converter (“TDC”) recorder. The clock of the TDC recorder is started as soon as a bunch of ions first enters the flight region of the Time of Flight mass spectrometer. Events recorded in response to the charge sensing discriminator output record the transit time of the ions through the flight region. A known 10 GHz TDC is able to record the arrival time of an ion at the ion detector to within ±100 ps.
In order to produce a complete mass spectrum, bunches of ions are repeatedly pulsed into the flight region. The transit times of all the ions through the flight region as recorded by the TDC recorder are used to produce a histogram of the number of ion arrivals as a function of the mass to charge ratio of the ions.
In a typical ion detector comprising a pair of microchannel plate detectors a bunch of electrons released from the microchannel plate detectors and incident upon a collection electrode arranged to receive the electrons will produce a signal input to a discriminator having an approximately Gaussian shape. Commonly such single ion peaks normally have a FWHM of between 0.5 and 3 ns. The average area of the ion peak will depend upon the gain of the ion detector. As will be appreciated by those skilled in the art, there will be a distribution of ion peak areas and thus ion peak intersites associated with the detection of ions using a microchannel plate detector even though the ions may have identical mass to charge ratios and velocities. This distribution arises due to the statistical nature of electron multiplication in the microchannel plate or other form of detector and the saturation characteristics of the multiplier. For a pair of microchannel plate detectors operated at a gain of approximately 107 this Pulse Height Distribution (“PHD”) is itself approximately Gaussian. The Pulse Height Distribution of a microchannel plate is generally described as the mean height of the signal as a percentage of the FWHM of the distribution of ion heights recorded. For this particular detector configuration a Pulse Height Distribution of 100-150% FWHM is common. If microchannel plate detectors are operated at low gain or discrete dynode electron multipliers or photo multipliers are used, then the Pulse Height Distribution has a different characteristic namely a negative exponential distribution. In any event it is apparent that there is a significant spread in ion signal intensities for single ion arrivals which must be somehow accommodated by the discriminator electronics.
Two main types of discriminators are commonly used in mass spectrometers. The simplest type of discriminator is a leading edge detector. The arrival time of an ion is recorded when the leading edge of an ion signal passes through or exceeds a predetermined intensity threshold. A count of 1 is then added to an histogram of intensity against flight time at the particular flight time associated with the ion signal crossing the intensity threshold. Digital electronics within the architecture of a multi stop Time to Digital Converter recorder are arranged to respond when the signal from the collection electrode (after amplification) exceeds that of the pre-set intensity threshold.
The other main type of discriminator is a Constant Fraction Discriminator (“CFD”) or zero crossing (i.e. peak top) discriminator. The arrival time of an ion is recorded when the ion signal exceeds or reaches a predetermined percentage of the maximum height of the ion signal. In the particular case of a peak top discriminator this fraction is 100% of the maximum height of the ion signal. Zero crossing refers to the point at which the first differential of the ion signal crosses zero.
There are two main drawbacks to using digital leading edge detection discriminators. A first problem is that the Pulse Height Distribution associated with an ion detector leads to a time spread or jitter in the time recorded for ion arrivals. For example, a first ion arriving at the ion detector at a time T1 will produce an ion signal having a maximum height H1. Such an ion signal will pass through a pre-set intensity threshold at a time T1′ and an event will be recorded in the closest corresponding time bin of the TDC. However, a second ion arriving at the ion detector at an identical time T1 may produce an ion signal which has a maximum height H2 which is greater than H1. Accordingly, such an ion signal will pass through the pre-set intensity threshold at a slightly earlier time T1″. The event as recorded by the TDC will therefore be recorded in an earlier time bin of the TDC to that of the first ion. The magnitude of this time jitter is related to the gradient of the leading edge of the ion signal and the Pulse Height Distribution of the detector. This effect leads to a decrease in the mass resolution of the final histogram and hence of the mass analyser.
A second problem with using a leading edge detection discriminator is that the ion signal must also drop below the same pre-set intensity threshold before another ion can be detected i.e. before the leading edge of a second ion signal due to another ion arriving at the ion detector can be recorded. For single ion peak widths of 2.5 ns FWHM this can lead to a dead-time of up to 5 ns. This dead-time refers to the time after which an ion has arrived at the ion detector and is being recorded and during which time no further ion arrivals can be recorded.
Multi stop TDCs should ideally be operated such that the input signal remains above the pre-set intensity threshold for approximately two time bins for an event to be recorded. In addition, the signal should remain below the pre-set intensity threshold for two time bins before a second ion arrival event can be recorded. This requirement leads to an inherent dead-time associated with TDCs related to the speed of digitisation. The dead-time associated with a single ion peak width is generally larger that the inherent dead-time of a TDC itself when clock rates >1 GHz are used.
If two ions have identical mass to charge ratios and arrive at an ion detector from the same bunch of ions pulsed into the time of flight region and arrive at the ion detector during one dead-time period, then the arrival of the second ion will not be recorded. If the analyte signal is particularly intense then the number of ions having the same mass to charge ratio in the same ion bunch pulsed into the time of flight region may be correspondingly large with the result that a significant proportion of ions arriving at the ion detector will not be detected. The mass to charge ratio value measured in the final mass histogram will therefore be shifted to lower mass to charge ratio and the total number of ions recorded will be less than the true number of ions arriving at the ion detector. Furthermore, when more than one ion arrives at the ion detector separated in time by less than the FWHM of a single ion pulse, then the resulting ion signals will combine to produce an ion signal input to the discriminator which is generally larger than that for a single ion arrival. Using a fixed pre-set intensity threshold to determine ion arrival time will therefore lead to an additional systematic shift to lower recorded mass to charge ratio.
It is possible to address some of these problems using a Constant Fraction Discriminator set to record an ion arrival when the ion signal exceeds a certain percentage of the maximum peak height. This enables the jitter associated with the Pulse Height Distribution of the ion detector to be minimised. Similarly, the systematic shift to low mass to charge ratio associated with the heights of multiple ion arrivals will also be minimised.
Using a peak top discriminator (which is essentially a Constant Fraction Discriminator set to record an ion arrival when the ion signal is at 100% of the maximum height) enables the arrival time jitter and mass to charge ratio shift related to single or multiple ion peak heights also to be minimised. In addition, an improved measurement of the mean ion arrival time for overlapping multiple ion arrivals can be obtained. If two ions arrive at the ion detector from the same bunch of ions and produce ion signals having identical heights and areas, then if the individual ion signals are separated in time by less than the FWHM of a single ion peak, then the two ion signals will combine to produce a resultant ion signal having twice the area of an individual ion signal. Although a peak top discriminator should in theory determine the mean arrival time of the two ions, in reality because the heights and thus areas of the two ion signals are unlikely to be exactly identical, then the peak top measurement for multiple ion arrivals will be subject to some statistical variation. This variation will though tend to be averaged in the final histogram. However, although Constant Fraction Discriminators and peak top discriminators have certain advantages compared to leading edge detectors, they also suffer from dead-time problems. In general there is a period of about 5-10 ns after an ion arrival is recorded during which no further ions arrivals can be recorded. In the case of a Constant Fraction Discriminator this leads to a systematic shift in the mass to charge ratio recorded in the final histogram. This shift will though not be quite as pronounced as the equivalent situation using a fixed pre-set intensity threshold leading edge detection discriminator.
In the case of a peak top discriminator, a systematic shift to low mass to charge ratio is only evident when the spread of ion arrivals in the final histogrammed peak (equivalent to the mass resolution of the instrument) exceeds a certain value. For illustration, if two ions arrive from the same ion bunch separated in time by more than the FWHM of a single ion peak, then the resultant ion signal will have two local maxima. Using a peak top discriminator only the first maxima will be recorded if the second maxima falls within the dead-time of the first (which is often the case). This again leads to a systematic shift to lower mass to charge ratio in the final histogram.
In all cases only one event may be recorded during one dead-time period. When significant numbers of ions arrive at substantially the same time the number of ion arrivals recorded in the final histogram will be less than the total number of ions actually arriving at the ion detector.
For these types of ion counting systems it is known to attempt to correct the mass to charge ratios and ion signal intensities reported in the final mass histogram using a method of dead-time correction. Dead-time correction may, for example, be applied to the ion count in each time bin of the final mass histogram or dead-time correction may be applied to individual mass spectral peaks based upon a predetermined look-up table. Further discussion of dead-time correction techniques is given in WO 98/21742 (U.S. Pat. No. 6,373,052) Hoyes, et al. The latter method allows real time correction of mass spectra and allows data from detailed Monte-Carlo modelling of the characteristics of individual discriminators and detector Pulse Height Distributions and output peak widths and shapes to be accommodated.
Dead-time correction, however, cannot accurately be applied when the ion signal intensity is changing dynamically during the time taken to accumulate complete mass spectra. If the ion intensity is changing in a known way this can be incorporated to some extent into the dead-time model. However, in reality, the ion intensity tends to change in an unpredictable manner and hence the average amount of correction to be applied can only be approximated by examining the rate of change from mass spectra to mass spectra as the experiment proceeds. For example, as analyte elutes from a chromatographic inlet its intensity will be changing during the time frame of a single histogram. Similarly, for systems using RF multipole rod set ion guides as ion-transfer devices, the transmission characteristics of the ion guide may vary during the time necessary to accumulate a histogram. This allows a broad cross section of ions having different mass to charge ratio values to be transmitted. The intensity of individual mass to charge ratio values within this histogram period will be changing at different rates during this procedure. Complex models are required in order to attempt to accommodate these changes to allow the amount of dead-time correction to be approximated. This can lead both to mass and intensity errors. The accuracy and precision required for dead time correction of mass to charge ratio value is often in the order of ±1-5 ppm. However, for quantitative work the accuracy and precision for intensity correction is generally of the order of ±5-10%. It can be seen therefore that relatively crude approximate models for dead time correction may suffice for intensity correction but lead to unacceptable errors in mass measurement.
It is therefore desired to provide an improved ion detection system and method of determining the ion arrival time at an ion detector.